Phase II study of weekly oxaliplatin and high-dose infusional 5-fluorouracil plus leucovorin in pretreated patients with metastatic colorectal cancer.

BACKGROUND: Chemotherapy with oxaliplatin, fluorouracil (5-FU) and leucovorin (LV) has proven efficacy in patients with advanced colorectal carcinoma (CRC), although the optimal dosage and administration schedule are still unclear. This phase II trial investigated the tolerability and activity of weekly oxaliplatin, high-dose infusional 5-FU and LV in pretreated patients with metastatic CRC. MATERIALS AND METHODS: Patients received weekly courses of i.v. oxaliplatin 50 mg/m2 (1-h infusion), LV 100 mg/m2 (1-h infusion) and 5-FU 2100 mg/m2 (24-h infusion) until disease progression or unacceptable toxicity. NCI-CTC criteria were used for assessment of side-effects (at each cycle) and WHO criteria for assessment of tumour response (every 8 cycles). For descriptive purposes, time to progression, overall survival and duration of objective response were also calculated. RESULTS: Forty-four patients were enrolled and received a total of 606 cycles (median 13/patient, range 4-33), and 70% of courses (421/606) were delivered at 100% of the planned dose. The most frequent side-effects were gastrointestinal and neurological and incidence rates were: diarrhoea 66% (grade III: 29%), nausea/vomiting 54%, neurotoxicity 34% (grade III: 2%), fatigue 27%, mucositis 22%, leucopenia 14%. No grade IV toxicity was observed. Objective response rates were: partial response 23% (10 patients), stable disease 59% (26) and progressive disease 11% (5). Median time to progression was 7 months, overall survival 13 months and the duration of partial response and stable disease were 9 and 6 months, respectively. CONCLUSION: The study demonstrated that this regimen has a favourable tolerability profile and is an active combination in the pretreated metastatic CRC patient, deserving further evaluation in phase III trials.

Intraperitoneal mitoxantrone: a feasibility and pharmacokinetic study.

Fractionated doses have been advocated to prevent chemoperitonitis after intraperitoneal infusion of mitoxantrone. Patients with peritoneal carcinomatosis of various origin underwent surgery, including intestinal resections, with minimal residual disease. Peritoneal mitoxantrone in 1000 ml/m(2) saline was planned on the first post-operative day in groups of four patients (5 mg/m(2) for 3 and 5 days, 7.5 mg/m(2) for 3 and 4 days, 10 mg/m(2) for 2-4 days, if possible). Due to dose-limiting myelosuppression, only one and three patients received the 7.5-mg 4-day and 10-mg 3-day regimens, respectively. A total of 20 patients were consequently treated. Neither major complications nor severe pain were observed. Pharmacokinetics were completed on the 1st day in five 5-mg and five 10-mg patients, on the 5th day in three 5-mg patients, and on the 3rd day in one 10-mg patient. On the 1st day, mean peritoneal peak concentrations of mitoxantrone resulted 1.45 +/-0.56 (range 0.48-1.9) and 1.9+/-0.85 (range 1.27-3.13) microg/ml in the 5-mg and 10-mg patients, respectively. Mean dialysate/plasma exposure (AUC) ratio was 115. Even in patients with sutures, early post-operative fractionated intraperitoneal mitoxantrone appears feasible and safe, with a high local advantage, for up to 5 days of treatment and a maximum tolerated total dose of 20-25 mg/m(2).

Sucralfate in the treatment of chemotherapy-induced stomatitis: a double-blind, placebo-controlled pilot study.

BACKGROUND: The study was a double-blind, placebo-controlled, randomised pilot study to assess the efficacy of sucralfate gel in the treatment of chemotherapy-induced mucositis. PATIENTS AND METHODS: At the onset of stomatitis, forty patients received sucralfate gel (1 gr.) or placebo and were instructed to apply the gel over oral mucosas, 3 times daily. RESULTS: Objective response was observed in 14 patients (11 complete response+3 partial response) and in 15 patients (10 CR+5 PR), in the sucralfate and placebo arms, respectively; (p = NS). Analysis of VAS (visual analogue scale) scoring of pain did not detect any statistical difference between the two groups. No important side-effects were observed. Twelve out 21 patients who obtained a complete resolution of stomatitis (5 out of 11 and 7 out of 10 in the sucralfate and in placebo arms, respectively) received further treatment at the subsequent course of chemotherapy; prevention of mucositis was observed in 4 patients in the sucralfate arm and in 6 patients in the placebo arm, respectively. CONCLUSION: In the present pilot study, sucralfate did not demonstrate a significant advantage in comparison to the placebo in the treatment of chemotherapy-induced stomatitis.

Reduction of cisplatin nephrotoxicity by procainamide: does the formation of a cisplatin-procainamide complex play a role?

Procainamide protects mice bearing P388 leukemic cells against the toxicity of cisplatin without diminishing antitumor activity. The mechanism of action of procainamide protection was investigated both in vitro and in vivo. HPLC studies showed that procainamide forms a complex with cisplatin in vitro that has a UV spectrum similar to that of DPR, a triamine platinum complex that contains procaine as ligand. We report here the effect of the reaction product of cisplatin and procainamide on both cisplatin-induced DNA interstrand cross-links (ISCLs) and on the total DNA platination of isolated DNA. Total DNA platination in vitro of isolated DNA was increased by 113% (P <.01) and 17% (P <.05) after incubation times of 1.75 and 6 h, respectively, compared with products from the reaction of cisplatin with water. Furthermore, the reaction product of cisplatin and procainamide was bound to DNA to a significantly greater extent than was cisplatin itself. ISCLs were decreased by 41% when this drug combination was incubated with DNA for 1.75 h, but no changes were observed after incubation for 6 h. We also examined the influence of the time interval between administration of cisplatin and procainamide on normal kidney injury, the renal distribution and urinary excretion of platinum, and the formation of cisplatin-DNA adducts in renal tissue of Sprague-Dawley rats after i.p. administration of 7.5 mg/kg cisplatin either with or without procainamide. The plasma concentrations of urea and creatinine and kidney histology demonstrated that procainamide provided effective protection in vivo in the rat when administered either simultaneously or at 0.5 and 1 h before or after cisplatin. The protection was accompanied by both higher renal levels of platinum and cisplatin-DNA adducts and by an increase in the formation of ISCLs. Moreover, a dose-dependent reduction of urinary excretion and concentration of platinum was also observed. We propose that procainamide, after accumulation in the kidney, may coordinate with cisplatin to form a less toxic DPR-like complex that renders rats less susceptible to cisplatin-induced toxicity.

Sequence effect of epirubicin and paclitaxel treatment on pharmacokinetics and toxicity.

PURPOSE: Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics. PATIENTS AND METHODS: Patients receiving epirubicin 90 mg/m(2) by intravenous bolus followed by paclitaxel 175 mg/m(2) over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters. RESULTS: Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL. h v 1,717 ng/mL. h; P =.002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P =.012). No difference was detected in paclitaxel pharmacokinetics. CONCLUSION: Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.

Cisplatin combined with tiopronin or sodium thiosulfate: cytotoxicity in vitro and antitumor activity in vivo.

We have previously reported that the thiol compound tiopronin protects rat kidneys in vitro against the toxic activity of cisplatin. The influence of tiopronin and sodium thiosulfate (STS) on the cytotoxicity of cisplatin has been investigated on P388 leukemic cells in vitro after 3 days. The combination has also been investigated in vivo in BDF1 mice bearing a P388 s.c. tumor. In contrast to STS, tiopronin did not significantly reduce the cytotoxic activity of cisplatin in vitro and nor did it affect the uptake of platinum (cisplatin-derived), binding to DNA or the percentage of interstrand cross-links (%ISCL) formation. The co-administration of cisplatin (4 mg/kg) and tiopronin (150 and 300 mg/kg) to BDF1 female mice bearing a s.c. P388 tumor produced a significant reduction in tumor growth similar to that of a single 6 mg/kg dose of cisplatin. Interestingly, pre-incubation in vitro of either tiopronin or STS for 2 h with the species formed from cisplatin by hydrolysis demonstrated their ability in inhibiting the cytotoxicity of these reactive platinum products. These results indicate that tiopronin does not reduce the cytotoxicity of cisplatin in vitro, as STS does. This may be, at least partly, because of a different effect of the two thiol compounds on the cellular uptake and binding of platinum to DNA. Notably, tiopronin substantially reduced tumor growth in mice treated with a non-toxic dose of cisplatin (p < or = 0.0277), suggesting some positive influence of this thiol compound on the antitumor properties of cisplatin. The ability of tiopronin to protect in vitro against the cytotoxicity of the aquation products of cisplatin may be related to its nephroprotective effect.

Combination of cisplatin-procaine complex DPR with anticancer drugs increases cytotoxicity against ovarian cancer cell lines.

DPR, cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate, is a newly developed water-soluble platinum compound which possess minimal cross-resistance to cisplatin and shows relatively less side effects. In an attempt to establish whether the combination of DPR with other conventional anticancer drugs would be of any benefit we assessed in vitro the cytotoxic effects of combinations of DPR with the antimetabolites 5-fluorouracil (5-FU) and methotrexate (MTX), the alkylating agents mitomycin C (MMC) and cisplatin, the antimicrotubule agent taxol (TAX), and the intercalating agent of the anthracycline group doxorubicin (DOX) on murine M5076 ovarian reticulosarcoma and human A2780 ovarian carcinoma cells. These agents were selected because of their common use in the clinic and because they represent four distinct categories of antineoplastic mechanisms. Cells were incubated for 72 h in the presence of single or combined drugs, and the cytotoxic effect was determined by the MTT assay. The analysis of combination treatment was made by the isobole method. In human A2780 cells, an overall synergy was found for DPR combined with 5-FU, DOX and cisplatin. Synergistic effects were also observed for most combinations with MTX or MMC. A DPR concentration-dependent additivity and antagonism was seen at the highest MTX concentration (1 microM), while additive effects were observed for the combined treatments of DPR and low concentrations of MMC (0.008 and 0.0016 microM). Additive effects were also observed for the association of DPR and TAX over most combinations tested. In murine M5076 cells, synergism was the prevailing result observed when DPR was combined with 5-FU, DOX, MMC or cisplatin. When administered together with MTX we observed additivity over most combinations tested. These findings suggest that DPR, when simultaneously administered with standard anticancer agents, may be advantagious for cytokilling.

Effect of the cisplatin-procaine complex DPR in combination with several anticancer agents on murine P388 leukemic cells in vitro and in vivo.

We evaluated in vitro the antiproliferative activity of DPR (Fig. 1), a new cisplatin-derived compound, in combination with five conventional anticancer drugs: the antimetabolites 5-fluorouracil (5FU) and methotrexate (MTX), the alkylating agent mitomycin C (MMC), the antimicrotubule agent taxol (TAX) and the intercalating agent of the antracycline group doxorubicin (DOX), against murine P388 leukemic cells. MTT assay was used to determine growth inhibition after incubation of cells for 72 hours in the presence of single or combined drugs. The additive, synergistic or antagonistic nature of the combined drug effect was determined using the isobole method. In our cellular model, synergism was the prevailing result observed when DPR was combined with MMC. Conversely, antagonism was observed when DPR was combined with TAX. When DPR was administered together with the other antineoplastic drugs, the final effect was dependent on the concentrations of single agents. The study in vitro of the association between DPR and MMC was extended in vivo in BDF-1 female mice bearing i.p. P388 leukemic cells. Our data in vivo confirmed those obtained in vitro, demonstrating the therapeutic advantage of the association of ineffective doses of DPR (2 and 7 mg/kg) and MMC (3.2 mg/kg) over the administration of MMC alone.